Pyrrolo(1,2,3-alpha epsilon)quinoxalin-2(3h)-ones and related compounds

ABSTRACT

THIS INVENTION CONCERNS PYRROLO(1,2,3-DE)QUINOXALIN2(3$) - ONES AND RELATED COMPOUNDS WHICH ARE PHARMACOLOGICALLY ACTIVE AS CENTRAL NERVOUS SYSTEM DEPRESSANTS.

United States Patent 01 hoe 3,813,392 PYRROL(1,2,3-de)QUINOXALIN ZOE-ONES AND RELATED COMPOUNDS John H. Sellstedt, 266 Iven Ave., St. Davids, Delaware,

Pa. 18327; Milton Wolf, 1058 Windy Knoll Road, West Chester, Pa. 19380 No Drawing. Original application June 9, 1969, Ser. No. 831,723, now abandoned. Divided and this application May 15, 1972, Ser. No. 252,990

Int. Cl. C07d 51/78 US. Cl. 260-250 R 3 Claims ABSTRACT OF THE DISCLOSURE This invention concerns pyrrolo[l,2,3-de]quinoxalin- 26g) ones and related compounds which are pharmacologically active as central nervous system depressants.

This application is a division of our prior, copending application, Ser. No. 831,723, filed June 9, 1969 now abandoned.

This invention relates to new and novel quinoxalines. More particularly it relates to pyrrolo[1,2,3-de]quinoxalin- 2(3g)-ones and related compounds which in standard and accepted biological tests have demonstrated usefulness as central nervous system depressants.

The new and novel compounds of the present inven tion are exemplified by those having the formula:

wherein R and R are selected from the group consisting of hydrogen, nitro, amino, carboxy, cyano, carbamyl, sulfamyl, trifiuoromethyl, halogen, lower alkyl, lower alkoxy, lower alkylthio, carb(lower)alkoxy, lower alkylsulfonyl, carboxy(lower)alkyl, lower alkanoylamino, di(lower) alkylamino, phenyl, halophenyl, lower alkylpheny, lower akoxyphenyl, phen(lower)alkyl, phen(lower)alkoxy, morpholino, pyridyl, furyl, and naphthyl; & and R when taken separately are selected from the group consisting of hydrogen, cyano, carboxy, carbamyl, lower alkyl, hydroxy (lower) alkyl, carb (lower) alkoxy, carb (lower) alkoxy(lower)alkyl, carboxy(lower)alkyl, di(1ower)alkylamino(lower)alkyl, phenyl, hydroxyphenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl, phen(lower) alkyl, benzoxyphenyl, pyridyl, furyl, and naphthyl; R and R, when concatenated and taken together with the two carbon atoms to which they are attached complete a ring selected from the group consisting of l-(lower) alkyl 1,2,5,6 tetrahydro 3,4 pyridindiyl, 4,5 dihydro- (g benzocyclohepten 1,2 ylene, 1 cycloalken- 1,2 -ylene containing from about 5 to about 12 carbon atoms, 1 (lower)alkyl l cyclohexen 1,2 ylene and 3,4 dihydro 1,2 naphthylene; and R is selected from the group consisting of hydrogen, lower alkyl, cyano (lower) alkyl, phen (lower) alkyl, morpholino (lower) alkyl, lower alkylamino (lower) alkyl, di (lower alkylamino lower)alkyl, N (lower)alkyl N' (lower)alkanoylamino (lower)alkyl, aziridinyl(lower)alkyl, azetidinyl(lower) alkyl, azolidinyl(lower)alkyl, azinyl(lower)alkyl, azepinyl(lower)alky, 1 (lower)alkylpiperazinyl(1ower)alkyl, l phenylpiperazinylflower)alky, 1 halophenylpiperazinyl(lower)alky1 and 1 phen(lower)alkylpiperazinyl(1ower)alkyl. As employed herein the terms lower alkyl,

) 3,813,392 Patented May 28, 1974 lower alkoxy, lower alkanoyl and the like are meant to include both branched and straight chain hydrocarbon groups having from one to about seven carbon atoms. The term halogen as used herein is meant to include chlorine, bromine, iodine and fluorine. Typical examples of these compounds are:

The new and novel compounds of the present invention may be prepared by the process which is exemplified by the following reaction scheme:

1 H N Reduction H N I (2) Cyclization,

N--N 0 R30 0 CHzRl l R1 R1 N r I I" 1 R2 R: (I) (I (III) /Alkylat1on,

l I l R,

wherein R R R R and R are defined as above and X is a halogen. The reduction-cyclization reaction is effected by contacting a l-nitroso-3,4-dihydroquinoxalin- 2(1g)-one (I) with zinc dust in acetic acid for about one-half hour at about ambient temperatures. Thereafter, the reduced mixture is contacted with an appropriate ketone (II) at about reflux temperatures for a period of up to about thirty minutes to afford an appropriate l-unsubstituted product (III). Preferably this reaction is conducted in glacial acetic acid. When the reduction-cyclization reaction is complete, the l-unsubstituted product (III) is separated by conventional recovery procedures e.g. filter the reaction mixture, wash the cake with acetic acid and a liquid alkanol and crystallize the l-unsubstituted product (III) from a suitable solvent, such as, dimethylformamide or dimethylacetamide.

The alkylation reaction is effected by admixing the above-prepared l-unsubstituted product (III) with hexane Washed fifty percent sodium hydride, in an anhydrous, reaction-inert solvent, e.g. dimethylformamide. To this mixture, there is added a solution of an appropriate halide (IV) in an anhydrous, reaction-inert solvent, e.g. dimethylformamide at a temperature range from about 70 C. to about 90 C. for a period o up to about two hours. When the alkylation is complete, the resulting 1- substituted product (V) is recovered by standard techniques. For example, the solvent is evaporated to afford a residue which is purified and then crystallized from a suitable solvent, e.g. an alkanol.

The 1-nitroso-3,4-dihydroquinoxalin-2(lgyones (I) employed as starting materials in the above-described process are prepared by the procedure of Perkin, W. H. and Riley, G. C. in J. Chem. Soc., 2399 (1923). The ketones (II) and halides (IV) employed in these reactions are commercially available or are easily prepared by processes well known in the chemical art.

The new and novel l-unsubstituted (III) and l-substituted (V) products of this invention possess valuable pharmacological activity. In particular, these compounds in standard pharmacological procedures demonstrate nervous system activity and are useful as depressants. Because of this property they are of particular importance in producing a calming eifect in animals.

In the pharmacological evaluation of the central nervous system depressant compounds of this invention the in vivo etiects of the compounds of this invention are tested as follows:

The compound is administered orally and intraperitoneally to three mice (14- to 24 grams) at each of the following doses: 400, 127, 40 and 12.7 mg./kg. The animals are watched for a minimum of two hours during which time signs of general stimulation (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration) and autonomic activity (i.e., miosis, mydriasis, diarrhea) are noted. The animals are tested for changes in reflexes (i.e., flexor, extensor) and are rated by use of a pole climb and inclined screen for the presence of sedation-ataxia. The Eddy Hot-Plate Method [Nathan B. Eddy and Dorothy Leimbach, J. Pharmacol. Exper. Therap. 107, 385 (1953)] is used to test for analgesia. The experiment is terminated by subjecting each animal to a maximal electroshock to test for anti-convulsant activity.

The compounds of this invention in the above test procedure induce decreased motor activity and decreased respiration when administered at a dosage range of 12.7 to 400 mg./kg. There were no deaths in the test animals at the highest dose used, 400 mg./kg. orally and intraperitoneally.

The l-unsubstituted products (III) of the present invention are also useful intermediates in the preparation of the corresponding l-substituted products (V) hereof. Further, when tested by the procedure set forth in the Cancer Chemotherapy Reports Number 25, the following l-substituted products (V) of the present invention have demonstrated activity as anti-tumor agents when administered to rats at an intraperitoneal dosage range from about 62.5 to about 175 rug/kilo of body weight:

1- (3-dimethylaminopropyl) -6-ethyl-5-phenyllg-pyrrolo[ 1,2,3-de] quinoxalin-ZGE) -one;

1- (3-dimethylamino-2-methylpropyl) -6-eth yl-S-phenyl- 1 H -pyrro1o[1,2,3-de]quinoxalin-2(3I )-one;

1- (Z-dimethylaminoethyl -6-ethyl-5-phenyl- III-pyrrolo [1,2,3-de] quinoxalin-2( 3g -one;

1- (2-diethylaminoethyl -6-ethyl-5 -phenyllg-pyrrolo [1,2,3-de] -quinoxalin-2 35) -one;

6-ethyl-5-phenyl- 1- 3-( 1-pyrrolidinyl)-propyl] 1gpyrrolo 1,2,3-de] quinoxalin-Z 35) -one;

1- 3-dimethylaminopropyl) -5- (p-methoxyphenyl) -6- methyl-lg-pyrrolo-[1,2,3-de]quinoxalin-2(3g) one;

S-(p-benzyloxyphenyl) -1- 3-dimethylaminopropyl) -6- methyl lg-pyrrolo[ 1,2,3-de] quinoxalin-ZGI-I) -one;

l-( 3-dimethylaminopropyl) -5-(p-hydroxyphenyl -6- methyl- 1 II-pyrrolo[ 1,2,3-de] quinoxalin-Z 3H) -one;

6-methyll- (Z-dimethylaminoethyl) -5-phenyl- 1gpyrrolo):1,2,3-de]quinoxalin-2(3g)-one;

3 (Z-dimethylaminoethyl) 4,8,9, 10, 11,12-hexahydrol H -cycloocta [4,5 1pyrrolo 1,2,3-de] quinoxalin-Z (3H) -one;

S-benzyl- 1- Z-dimethylaminoethyl) G-phenyl- 1gpyrrolo[ 1,2,3 -de] quinoxalin-Z 3H) -one; and

1( Z-dimethylarninoethyl) -6-ethyl-5-phenyl-lpyrrolo[1,2,3-de]quinoxalin-2-(311 )-one.

Still further, some of the l-substituted products (V) of the present invention have also deconstra-ted immunosuppressive activity by their ability to inhibit experimentally induced allergic encephalomyelitis in rats when administered at an intraperitoneal dosage range of about to about 200 mg./ kilo of body Weight. This immunosuppressive activity was tested by procedures of Brandriss, M. W. Science 1402186, 1963 and Levine er al. Proc. Soc. 1141220, 1963. The compounds which have demonstrated this activity are: 1-(3dimethylaminopropyl)-6-ethyl-5- phenyllg-pyrrolo l,2,3-.de] quinoxalin-2 3g) -one; 1- (2- dimethylaminoethyl) 6 ethyl 5 phenyl-lg-pyrrolo [1,2,3-de]quinoxalin-2(3E)-one; and 1-(3 dimethylaminopropyl) 5 (p hydroxyphenyl)G-methyl-IH- pyrroloi1,2,3-de]quinoxalin-2(3E)-one.

When the compounds (III and V) of this invention are employed as central nervous system depressants they may be administered to warm-blooded animals, e.g. mice, rats, rabbits, dogs, cats, monkeys, etc. alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in the solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present central nervous system depressants will vary with the form of administration and t the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum eliect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmtul or deleterious side eifects.

EXAMPLE I l-nitroso 3,4 dihydroquinoxalin-2(lgyone (20 g., 0.113 mole) is stirred in glacial acetic acid (300 ml.) and zinc dust (40 g.) is added in portions while keeping the temperature below 25 C. When all of the zinc has been added the mixture is stirred an additional twenty minutes. Then the reduction mixture is filtered into a one-liter flask containing propiophenone (15.2 g., 0.113 mole), and

the zinc cake washed with acetic acid (100 ml.) before it dries. The solution is stirred and slowly heated to reflux until crystals form. If crystals form before reflux, the mixture is refluxed for ten minutes, cooled to 20 C. in ice, filtered and washed with acetic acid then ethanol, giving light yellow crystals (11.2 g., 36%), M.P. 285- 288 C. (uncorr.) which crystallized from dimethylformamide, give white crystals of 6-methyl-5-phenyl-lg-pyrrolo[1,2,3 de]quinoxalin 2(311) one (10.7 g., 35%), M.P. 288-290 C. (uncorr.).

Analysis.Calcd. for C H N O: C, 77.84; H, 5.38; N, 10.68. Found: C, 77.92; H, 5.31; N, 10.75.

EXAMPLE II Repeating the procedure of Example I, to react l-nitroso-3,4-dihydroquinoxalin-2(1)-one with an appropriate hereinafter listed ketone, the following products are obtained:

Ketone Product 3-benzoylpropionic acid. 2,3-dihydro2-oxo-5-phenyl-lIl-pyrrolo- [1,2,3-de]quinoxaline-6-acetic acid, M.P. 301 303 C. (decmp.), (16% yield).

cyclopentanone 8,9-d1hydro-1E,7H-cyclopenta[4, ]pyrrolo- [1,2,3-de]quinoxalin-2(3H)-0ne, M.P. 283- 285 C. (38% yiel -Tetralone 7,8-dihydro-1H-benzolalpyrazin0[3,2,1-jklcar{)azol-2(3g)-one, M.P. BBQ-311 C. (23% y1 Butyrophenone 6ethyl-5-phenyl-1g-pyrrolofl,2,3-de]quinoxalin-2(3H)-one, M.P. 245-246 O. (54% yield); Cyclododeeanone 7,8,9,10,11,12 13,14,15,16-decahydro 1E-cyc1ododeca.[4,5l-pyrrolo[1,2,3-de]qulnoxalin- 2(3g)-one, M.P. 247249 0., (56% yield). Phenyl-2-propanone. 5-methy1-6-phenyl-1g-pyrro1o[1,2,341e]quin- 0xallin-2(311)-one, M.P. 282-284 C (51% 371 Ethylacetoacetate 2,3-dihydro5-methyl-2oxo-1g-pyrrolo[1,2,3-

de]quinoxaline-6-carboxylic acid, ethyl ester, M.P. 266.5267.5 C. (15% yield). Benzoylacetonitrile-.-.- 2,3-dlhydro-2-oxo5-phenyl-1g-pyrrolo[1,2,3-

delquinoxaline-fi-carbonitrile, M.P. 312-313" C. (36% yield). 6-(2-hydroxyethyl)5-(p-methoxyphenyl)- 4-hydroxy-4-methoxybutyrophenone. 1H-pyrolo[1,2,3-de]quinoxalin-2(3g)-one,

acetate, M.P. l9920l C. (6% yield). Do 6-(2-hydroxyethyl)-5-(p-methoxy-phenyl)-1gpyrrololl,2,3-de)-quinoxalin-2(3g)-one, M.P. 231-233 C. (9 yield). 2-pentanone 6-ethy1-5 methyl-lg-pyrrolo(1,2,34ie1qulnoxalin-2(3g)-one, M.P. 217-219 C. (38% yield). Valerophenone 5-ph enyL6-propyl-1H-pyrrol0[1,2,3-de]quinoxallIi.(-i2)(3H)-OD8, M.P. 230230.5 C. (48% we m-Chloroproplophe- 5-(m-ehlorophenyl)-6 methyl-1g-pyrrolonone.

1,2,3-de]quinoxalin-2(3g)-one, M.P. 273- 276 C (60% yiel d). o-chloropropiophefi-(o-chlorophenyl)-6methyl-1g-pyrrolonone.

l,2,3de]quinoxalin-2(3H)-one, M.P. 219- 222 C. (28% yield).

Levulinic acid 2,3-dihydro5methyl-2-oxo-lfl-pyrrolo- [1,2,3-deIquinoxaline-G-acetic acid, M.P. 286287 C. (decornp), (28% yield).

phenone. 1,2,3-de]quinoxalin-2(3g)-one, M.P. 270- 273 C. (52% yield).

p-Mcthoxypropiophe- S-(p-methoxyphenyl)-6-methyl-lg-pyrrolonone.

[1,2,3-de]quinoxalin-2(3g)-one, M.P. 278- 281.5 C. (51% yield).

S-Epchlorophenyl)-6-methyl-1g-pyrrolo- 1,2,3- e]quinoxalin-2(3g)-one, M.P. 333- 336 C. (57% yield).

p-Chloropropiophenone.

EXAMPLE III 1 nitroso 3,4 dihydroquinoxalin-2(1g)-one (0.565 mole) is stirred in glacial acetic acid (1500 ml.) and zinc dust (200 g.) is added in portions while keeping the temperature below 25 C. When all of the zinc has been added, the mixture is stirred an additional half hour. Then the reaction mixture is filtered into a five liter flask containing 1,3-diphenylpropanone (0.565 mole), and the zinc cake washed with acetic acid (500 ml.). The reaction solution is stirred and slowly heated to reflux until crystals form. If crystals form before reflux, the mixture is refluxed for ten minutes, cooled in ice, filtered and washed with acetic acid then ethanol, giving crystals of S-benzyl- 6-phenyl-1g-pyrrolo[1,2,3 de]quinoxalin 2(3 I 1 one. M.P. 240-242 C. (55% yield).

Analysis.Calcd. for C H N O: C, 81.63; H, 5.36; N, 8.28. Found: C, 81.46; H, 5.34; N, 8.27.

EXAMPLE IV When the procedure of Examples I-III is repeated to react a 1-nitroso-3,4 dihydroquinoxalin-2( 1I)-one with an appropriate ketone, there is afforded compounds of the following formula:

R1 I N ,Qtll

wherein R R R and R are defined as follows:

R1 R3 R3 R4 Hydrogen- B-cyanop-Tclyl Propyl. B-chloro 9-chl0r0 p-BrornophenyL B-tritluoromethyl. Hydroge Carbomethoxy. 7-ethoxy 8-amino p-Hydroxy phenyl. Q-bromo S-carboxy. p-EthylphenyL- Hydrogen. B-cthy Hydro en Hydro p-lVethoiry p eny S-fluoro 9-su1famyl .do 8-nitro- Q-phenyl p-Iodophenyl Hydrogen. S-carbarnyl 9-metl1yltl1lo Hydrogen Valeryl. 7-butyl Hydro m n (in Oarbethoxy. 8-cthylthio.....-. 9-iodo Phenpropyl Hydrogen. S-methoxy Q-methoxy Hydrogen Dimethylaminoethyl. p-ChlorophenyL. Hydrogen -do Hydrogen. S-morpholino do. .do 2-pyrldyl. Q-methyl- 9-propoxy --do 2-naphthyl.

sulfonyl. Hydrogen Q-acetamido do Cyano. 8-ethylsulfonyl Q-acetyl do.. m-flucrophenyl 7-carbomethoxy B-benzyl..- do Naphthyl. S-dimethylamino- Hydrogen -do 2-furyl. B-pyridyl Q-butylthio Dimethyl Hydrogen aminoprouyl. Hydrogen 9-benzyloxy. Hydrogen Do. S-carbethoxy Q-p-bromo p-Butoxy Do.

phenyl. phenyl. 7-proplonyl Hydro en Hydrnven Phenethyl. 8-phenethyl do do Hydrogen. B-propionamido do .-do Oarbpropoxy.

EXAMPLE V l-nitroso 3,4 dihydroquinoxalin-2(ll 3 )-one (0.226 mole) is stirred in glacial acetic acid (600 ml.) and zinc dust (80 g.) is added in portions while keeping the temperature below 25 C. When all of the zinc has been added, the mixture is stirred an additional half hour. Then the reduction mixture is filtered into a one liter flask containing N-ethyl-4-piperidone (0.226 mole), and the zinc I Ketone Product 4-propylpiperidone 7,8,9,10-tetrahydro-8- ropyl-lg-pyridolaAz 4,5]pyrrolo[l,2,3-de qui noxalin-2(3fl)-one.

.c 11 2. A compound as described in claim 1 which is: 8- tert-butyl 7,8,9,10 tetrahydro 1g pyrazino[3,2,1-jk] carbazol-2(3g)-onc.

3. A compound as described in claim 1 which is: 7,8- dihydro-lg-benzo {a1 pyrazino[3,2, 1- jk] carbazol 2(3fl) one.

References Cited Perkin, et aL, J. Chem. Soc. (London), 123, 2399- 2408 (1923). a v.

12 Waterman et aL, Chem. Abstracts 37:8925. Shvedov et aL, Chem. Abstracts 72:121S77p (1970).

DONALD G. DAUS, Primary Examiner 5 R. D. MCCLOUD, Assistant Examiner US. Cl. X.R.

260-239 A, 239 B, 247.2 A, 268 PC; 424-250 

